Synthesis of analogues of the carboxyl protease inhibitor pepstatin. Effect of structure in subsite P3 on inhibition of pepsin.
A series of pepstatin analogues having minimum structural requirements for tight-binding inhibition has been synthesized and tested on porcine pepsin. Subtle changes in the geometry and size of side chains at the valine-1 position of pepstatin were found to dramatically affect inhibitor potency as well a the type of kinetic behavior observed. The inhibitors reported here can be grouped into two categories: the more potent inhibitors are slow-binding inhibitors, i.e., exhibit slow, time-dependent inhibition: the weaker inhibitors, with Ki values greater than 10(-8) M, are not time-dependent inhibitors. A minimum kinetic mechanism is proposed to account for the observed kinetic behavior.
D001665:Binding Sites; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D007700:Kinetics; D009842:Oligopeptides / Q000138:chemical synthesis*; D010434:Pepsin A / Q000037:antagonists & inhibitors*; D010436:Pepstatins / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D010436:Pepstatins; D010434:Pepsin A